1. Field of the Invention
The present invention relates to a novel pyrimidine derivative or a salt thereof, and a pharmaceutical composition, particularly, an agent for treating a kidney disease, containing said pyrimidine derivative or a pharmaceutically acceptable salt thereof. Although the pyrimidine derivative of the present invention exhibits substantially no or very weak antagonism to the angiotensin II receptor subtype 1 which participates in action to depress blood pressure, it can sufficiently improve a kidney disease.
2. Description of the Related Art
Recently, there is an increasing tendency of patients suffering from renal dysfunction. The reason is believed that a development of drugs appropriate to treat kidney diseases is behind with an increasing aged population or changes in living environment. Therefore, the drugs appropriate to treat kidney diseases have been strongly desired.
More particularly, a method for treating lesions accompanying diseases, i.e., the nosotropic treatment, is mainly used as yet for kidney diseases, such as nephritis, diabetic nephropathy or renal failure. For example, an antihypertensive, diuretic or anti-inflammatory agent, or dietary treatment, kinesitherapy or the like is mainly used. Because kidney diseases are accompanied with hypertension and the hypertension is believed to be one of factors aggravating kidney diseases, the antihypertensive agents are often used. Of the antihypertensive agents, the agents to inhibit production or function of angiotensin II are attempted in many cases. This is because that angiotensin II is believed to be a factor aggravating kidney diseases due to its activities to raise blood pressure and accelerate growth of interstitial cells in the kidney, and elimination of such a factor as much as possible is believed to improve the kidney diseases.
It is reported in J. Clin. Pharmacol., 30:155-158, 1990 that when the antihypertensive agent (such as enalapril or captoril), namely, the agent to inhibit the enzyme to convert angiotensin I to angiotensin II which exhibits the activity to raise blood pressure (angiotensin converting enzyme; ACE), i,e., the angiotensin converting enzyme inhibitor (ACEI), is used, blood pressure is lowered and the progress of renal dysfunction is improved. U.S. Pat. No. 5,071,867 suggests that because the improvement of the renal dysfunction is observed in rats suffering therefrom by administering the antihypertensive agent in an amount larger than that usually used to lower blood pressure, human will become endurable to a large dose if the dose is carefully and gradually increased, and to thereby enjoy the benefit of curing the renal dysfunction in human. On the other hand, it is pointed out in "Saishin Igaku (Latest Medicine)", 48: 1404-1409, 1993 that such agents have side effects such as dry-cough as their inherent properties, or are attended with danger to lower blood pressure and then cause acute renal failure, and therefore should be carefully administered.
Thereafter, an angiotensin II receptor antagonist (AGIIRA) was developed as a antihypertensive agent. Two kinds of the angiotensin II receptors, the subtype 1 and the subtype 2, are known at the present. Although the functions of the subtype 2 are not sufficiently elucidated, the subtype 1 is known to participate in blood pressure. Therefore, the subtype 1 receptor antagonist is a target of the development of the antihypertensive agent.
As the compounds which are antihypertensive agents exhibiting a strong antagonizing activity to the angiotensin II receptor, and at the same time, are examined for their action to kidney diseases, the imidazole derivative, 2-butyl-4-chloro- 5-(hydroxymethyl)-1-[[2'-(1H-tetrazol- 5-yl )biphenyl-4 -yl]methyl]imidazole (Dup753 or MK954) is known. When the imidazole derivative was administered to renal dysfunction model rats, it was effective against proteinuria and glomerulosclerosis, but at the same time the reduction of blood pressure accompanied (J. Clinical Invest., 90: 766-771, 1992). Further, when the above imidazole derivative was administered to hyperlipemia model rats, the kidney disease was improved in a lower dose without practical effect to blood pressure, but an evident reduction of blood pressure was observed at a large dose more effective against the kidney disease (Nephron, 65: 426-432, 1993).
Further, compounds having the structures similar to that of the above imidazole derivative are disclosed in Japanese Unexamined Patent Publication No. 63-23868, and U.S. Pat. No. 5,153,197, U.S. Pat. No. 5,128,355 and U.S. Pat. No. 5,155,118. Japanese Unexamined Patent Publication No. 63-23868 discloses that such compounds are effective against hypertension and congestive heart failure. U.S. Pat. No. 5,153,197 discloses that such compounds are effective against hypertension. U.S. Pat. No. 5,128,355 discloses that such compounds are effective against heart failure. U.S. Pat. No. 5,155,118 discloses that such compounds are effective against renal failure caused by non-steroid anti-inflammatory agent. However, all the imidazole derivatives disclosed in said Japanese Unexamined Patent Publication and U.S. Patents are characterized by a strong angiotensin II receptor antagonism, and have an activity to lower blood pressure.
EP 0475206A2 discloses the compounds having a pyrimidine skeleton and its application to kidney diseases. However, the pyrimidine compounds are characterized by a strong angiotensin II receptor antagonism accompanied by the lowering function of blood pressure. Further, it is reported in J. Pharmacol. Experimental Therapeutics, 267: 657-663, 1993 that when one of the pyrimidine analogues, 2-[N-propyl-N-[[2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]amino]pyridine-3 -carboxylic acid (A-81988), was administered to kidney disease model rats, proteinuria was improved, but at the same time, the reduction of blood pressure was observed. The above pyrimidine analogues exhibits the function to lower blood pressure due to the strong angiotensin II receptor antagonism, and therefore, there is a fear of acute renal failure or the like when administered to the person suffering from kidney diseases.
As above, hitherto, drugs having the function to strongly lower blood pressure were basically desired in the treatment of the kidney diseases by the antihypertensive agent. In the kidney disease, the hypertension is an important symptom to be improved. However, mere lowering of blood pressure is not favorable. It is important to maintain appropriate blood pressure. Thus, it is necessary to adjust blood pressure by combining the kinds and the doses of the antihypertensive agents in view of the symptom. However, continuous treatment with a sufficient dose is desired for the kidney diseases per se. Therefore, so long as a conventional antihypertensive agent is used, it is fundamentally impossible to appropriately adjust blood pressure and at the same time to effectively cure the kidney disease by the sole antihypertensive agent. One of such problems is, for example, the above acute renal failure caused by the antihypertensive agent used.